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Selective Knockout of Astrocytic Na + /H + Exchanger Isoform 1 is Neuroprotective in Ischemic Stroke Injury
Author(s) -
Begum Gulnaz,
Wang Shaoxia,
Zhao Hanshu,
Bhuiyan Mohammad Iqbal Hossain,
Nepomuceno Rachel,
Ye Qing,
Stolz Donna Beer,
Sun Ming,
Chen Yinhuai,
Shull Gary E,
Dandan Sun
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1224.21
Subject(s) - astrocyte , glial fibrillary acidic protein , chemistry , astrogliosis , aquaporin 4 , microbiology and biotechnology , pathology , endocrinology , biology , medicine , immunohistochemistry , biochemistry , central nervous system
We previously reported that Na + /H + exchanger isoform 1 (NHE1) plays a role in the dysregulation of ionic homeostasis in astrocytes under ischemic conditions. In this study, we created an Nhe1 flox/flox mouse line ( Nhe1 f/f ) with exon 5 of Nhe1 flanked with two loxP sites in order to selectively ablate NHE1 in astrocytes when crossed with cell‐type specific GFAPCreER T2 Cre‐recombinase mouse line. Gfap CreER/+ ;NHE1 f/f mice at P60–90 were treated with either tamoxifen (Tam, 75mg/kg/day, i.p.) or corn oil for 5 days to induce Cre recombination. 30 days post injection, mice underwent a transient middle cerebral artery occlusion (tMCAO) to induce ischemic stroke. With ultrastructural and immunocytochemical analyses at 2 days post‐tMCAO, we detected perivascular reactive astrocyte formation, extensive perivascular edema, swollen and vacuolated endothelial cells and damaged tight junctions in the Gfap CreER/+ ;NHE1 f/f mice treated with the corn oil, which was accompanied with AQP4 and laminin accumulation. In contrast, reduced AQP4 protein expression and less laminin accumulation were detected in the microvessels of the Tam‐treated Gfap CreER/+ ;NHE1 f/f mice. Selective knockout of NHE1 in GFAP + astrocytes also prevented reactive astrocyte formation, decreased S100β release, and reduced microvessel damage and the BBB leakage after ischemic stroke. The Gfap CreER/+ ;Nhe1 f/f mice treated with Tam exhibited smaller ischemic infarct and less pronounced neurological function deficits. Taken together, this is the first study to report that astrocytic NHE1 plays an important role in reactive astrocyte‐mediated ischemic brain damage. Support or Funding Information NIH R01 NS048216 (D.S)